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CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis
Anni Laine1,2, Srikar G Nagelli1,3, Caroline Farrington4,5
1Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
Cancer Research
|June 19, 2021
Summary
CIP2A drives basal-like breast cancer (BLBC) by coordinating DNA repair and cell division. Inhibiting CIP2A shows promise for treating BLBC, particularly triple-negative subtypes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Basal-like breast cancers (BLBC) exhibit homologous recombination defects, mitotic checkpoint issues, and rapid proliferation.
- CIP2A is identified as a potential key driver in BLBC development and progression.
Purpose of the Study:
- To investigate the role of CIP2A in the initiation and survival of BLBC.
- To explore the interaction of CIP2A with DNA repair proteins and its impact on cell cycle regulation.
- To evaluate CIP2A as a therapeutic target in BLBC.
Main Methods:
- Investigated CIP2A's role in mouse models of BLBC and HR-defective cells.
- Identified direct interaction between CIP2A and TopBP1.
- Assessed the effect of CIP2A inhibition on DNA damage response (DDR) and proliferation.
- Analyzed clinical data correlating CIP2A expression with patient prognosis in BLBC subtypes.
- Tested small-molecule reactivators of PP2A (SMAPs) in patient-derived xenografts.
Main Results:
- CIP2A is essential for DNA damage-induced BLBC initiation and survival of HR-defective BLBC cells.
- CIP2A interacts with TopBP1, influencing DNA repair protein recruitment and mitotic progression in damaged cells.
- High CIP2A expression correlates with poor prognosis in basal-like triple-negative breast cancer (BL-TNBC).
- SMAPs inhibit CIP2A transcription, mimic CIP2A deficiency in DDR, and reduce BLBC xenograft growth.
Conclusions:
- CIP2A is a critical nongenetic driver in BLBC, regulating the DNA damage-induced G2-M checkpoint and proliferation.
- Targeting CIP2A, potentially through SMAPs, represents a promising therapeutic strategy for BLBC, especially BL-TNBC.
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